Less than a year after Roentgen's demonstration of x-ray based imaging, two groups reproduced his findings and also proposed the use of x-ray contrast enhancing media allowing for greater differentiation between soft tissues and blood vessels. Since then, these contrast enhancing media, or “contrast agents,” have evolved over the past century to the current state of well tolerated and highly efficacious drugs used in the vast majority of patient CT examinations. The past half century has mainly focused on the development of agents with limited bio-toxicity and in some respects on agents that can provide enhancement of specific anatomical markers such as blood vessels and plaques.
The quantification of physiology however, has been principally the purview of other imaging modalities such as contrast enhanced glucose uptake quantified by positron emission tomography or MRI measurements of oxygen consumption. The choice of imaging modality has much to do with the risk to the patient, the unique physics associated with photon-mass interactions, radioactive decay, and nuclear spin. Additionally, the unique physics of each modality can yield relatively specific physiological insights.
However, three-dimensional imaging modalities have been unable to non-invasively and directly measure electrical activity inherent in many cell types including neural, cardiac, and skeletal muscle tissue. Instead, the electroencephalograph (EEG), electrocardiograph (ECG), and electromyograph (EMG) have received the majority of focus for measurement of electrical phenomena. All of these techniques are limited to a two-dimensional surface and rely on significant anatomical and morphological assumptions for “inverse problem” reconstruction of subdermal electrical activity. Even after all the assumptions are implemented, the reconstructed potentials are again fit to a surface and cannot yield significant information about the electrical activity within deeper layers of muscular or neurological tissue.
Likewise, previous imaging modalities have been unable to measure intracellular ion concentrations non-invasively and in-vivo. Again the limitation here is that there are no effective agents capable of transducing these biological parameters into a signal useful for three-dimensional reconstruction. One mechanism for imaging electrical activity, and thereby potentially even ionic concentrations, in three-dimensions has been demonstrated in isolated whole-heart preparations using voltage sensitive dyes. Briefly, a piece of muscular tissue is illuminated from both sides (transillumination), and a dye capable of changing its fluorescence properties in response to a change in membrane potential, is mapped with high temporal and spatial resolution cameras from either side of the heart. Mathematical assumptions are again employed to reconstruct activity within the wall of the heart. This technique however is unlikely to be employed in the body because voltage sensitive optical dyes emit and absorb ultraviolet through infrared excitation light sources, a light spectrum of energy insufficient for imaging deeper than a few millimeters to a centimeter.
As such, imaging modality for transducing biological phenomena in three-dimensions and other measuring techniques for biological phenomena, such as membrane potential or intracellular ionic concentrations, as well as other properties, continue to be sought.